104618-32-8Relevant articles and documents
Binding of O-alkyl derivatives of serotonin at human 5-HT1Dβ receptors
Glennon, Richard A.,Hong, Seoung-Soo,Bondarev, Mikhail,Law, Ho,Dukat, Malgorzata,Rakhit, Suman,Power, Patricia,Fan, Ermei,Kinneau, Diana,Kamboj, Rajender,Teitler, Milt,Herrick-Davis, Katharine,Smith, Carol
, p. 314 - 322 (1996)
In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1Dβ receptors (K(i) 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1Dβ K(i) = 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or β- carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1Dβ versus 5-HT1Dα sites; nevertheless, compounds 10 (recently shown to behave as a 5- HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.
Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
, (2021/02/12)
Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
Cobalt-Catalyzed Desymmetric Isomerization of Exocyclic Olefins
Lan, Yu,Liu, Qiang,Liu, Shihan,Liu, Xufang,Rong, Xianle
supporting information, p. 20633 - 20639 (2021/12/17)
Chiral cyclic olefins, 1-methylcyclohexenes, are versatile building blocks for the synthesis of pharmaceuticals and natural products. Despite the prevalence of these structural motifs, the development of efficient synthetic methods remains an unmet challenge. Herein we report a novel desymmetric isomerization of exocyclic olefins using a series of newly designed chiral cobalt catalysts, which enables a straightforward construction of chiral 1-methylcyclohexenes with diversified functionalities. The synthetic utility of this methodology is highlighted by a concise and enantioselective synthesis of a natural product, β-bisabolene. The versatility of the reaction products is further demonstrated by multifarious derivatizations.
A Short Synthesis of the 2-Bromo-N,9-dimethyl-6,7,8,9-tetrahydro-5 H-pyrido[2,3-b]indol-6-amine Building Block
Sreenivasachary, Nampally,Kroth, Heiko,Benderitter, Pascal,Barth, Wolfgang,Pfeifer, Andrea,Muhs, Andreas
supporting information, p. 2521 - 2526 (2019/10/16)
A concise synthesis of pharmaceutically useful (R)-tert-butyl N-(2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-6-yl)-N-methylcarbamate building block 11 is described. The racemic intermediate 17 was prepared in a single step from 2-bromo-6-(1-methylhydrazinyl)pyridine sulfate salt (14) and N,3,3-trimethyl-1,5-dioxaspiro[5.5]undecan-9-amine hydrochloride salt (16). Chiral separation of racemic intermediate 17 by diasteromeric salt recrystallization afforded the diasteromeric salt 18 in 37% yield, which was Boc-protected to afford building block 11. Thus, the process for the synthesis and chiral separation by diasteromeric salt crystallization allowed the synthesis of chiral building block 11 in kilogram quantities in 18% overall yield.
Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
-
Page/Page column 62, (2011/11/30)
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
The catalytic asymmetric Fischer indolization
Mueller, Steffen,Webber, Matthew J.,List, Benjamin
supporting information; experimental part, p. 18534 - 18537 (2012/01/31)
The first catalytic asymmetric Fischer indolization is reported. In the presence of a 5 mol % loading of a novel spirocyclic chiral phosphoric acid, 4-substituted cyclohexanone-derived phenylhydrazones undergo a highly enantioselective indolization. Efficient catalyst turnover was achieved by the addition of a weakly acidic cation exchange resin, which removes the generated ammonia. The reaction can be conducted under mild conditions and gives various 3-substituted tetrahydrocarbazoles in generally high yields.
SYNTHESIS OF (2-AMINO)-TETRAHYDROCARBAZOLE-PROPANOIC ACID
-
Page/Page column 12, (2010/08/04)
The present invention provides a new approach to the synthesis of 2-amino-tetrahydrocarbazole-propanoic acid, a key intermediate for the synthesis of Ramatroban. More specifically, a synthesis of 2-amino-tetrahydrocarbazole- propanoic acid which includes oxidizing an aminocyclohexanol to form an aminocyclohexanone, condensing the aminocyclohexanone to form a tetrahydrocarbazole, deprotecting the tetrahydrocarbazole to yield a racemic mixture of a tetrahydrocarbazole, resolving the racemic mixture to obtain a yield mixture with an enantiomeric excess of one enantiomer over another, alkylating the excess enantiomer to yield an alkyl ester, and hydrolyzing the alkyl ester to yield 2-amino-tetrahydrocarbazole-propanoic acid.
4-AZETIDINYL-1-HETEROATOM LINKED-CYCLOHEXANE ANTAGONISTS OF CCR2
-
Page/Page column 39, (2010/11/03)
The present invention comprises compounds of Formula (I). wherein: X, R1, R2, R3, and R4 are as defined in the specification. The invention also comprises a method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is type II diabetes, obesity and asthma. The invention also comprises a method of inhibiting CCR2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula (I).
PROCESS FOR PREPARING (S)-PRAMIPEXOLE AND ITS INTERMEDIATES
-
Page/Page column 16-17, (2008/06/13)
The present invention relates to an improved process for the preparation of (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole of formula (II) useful in the preparation of pramipexole or (S)-2,6-amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) and its pharmaceutically acceptable salts or solvates thereof. The present invention further provides a process for the preparation of Pramipexole and its pharmaceutically acceptable salts, hydrates, solvates thereof.
IMPROVED PROCESS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE TETRAHYDROBENZTHIAZOLE DERIVATIVE
-
Page/Page column 10; 16, (2008/06/13)
Improved process for the preparation of the intermediate compound of formula II for formation pramipezole of formula (I) as well as the biological active tetrahydrobenzothiazole compound of formula (I) and/or its pharmaceutically acceptable salts or solvates.
